RON alternative splicing regulation in primary ovarian cancer

The proto-oncogene recepteur d'origine nantais (RON, MST1R) and its alternatively spliced variants are involved in various tumor biological processes, such as cell motility, adhesion, proliferation, apoptosis and epithelial-to-mesenchymal transition (EMT). RON overexpression and the occurrence of specific alternatively spliced RON isoforms have been detected in ovarian cancer. In the present study, we evaluated the role and regulation of cancer-related RON splicing isoforms in primary ovarian cancer. Expression of RON variants (RON Delta 165, RON Delta 160) was determined in 45 primary ovarian cancer and 4 physiological ovarian tissue specimens by RT-PCR and western blot analysis. The results were correlated to clinicopathological parameters. Additionally, expression of splicing factors with known involvement in RON alternative splicing regulation was examined. Increased RON levels were detected in all tumor samples (P=0.001) without differences between the primary tumors and metastases. Alternative RON variants were present in the majority of tumor samples (39 of 45; 86.67%). Potential RON Delta 165 occurred more often (82.22%) than potential RON Delta 160 or RON Delta 155 (24.40%). Several significant correlations of RON and splicing factor expression [e.g. ASF/SFRS1 (P=0.035)] were detected. Correlations of RON expression to clinicopathological parameters were not observed. Significant splicing factor interactions (e.g. SRp55/SRp75: P<0.001) were observed in tumor samples with alternative RON splicing. Our data demonstrated upregulated RON isoform expression and significant changes in splicing factor expression in primary ovarian cancer. These findings account for an essential regulatory interplay of splicing factor-driven alterations in the RON alternative splicing pattern with subsequent tumor biological consequences in ovarian cancer.